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Dopaminergic neurons in the substantia nigra (SN) expressing SUR1/Kir6.2 type ATP-sensitive potassium channels (K-ATP) are more vulnerable to rotenone or metabolic stress, which may be an important reason for the selective degeneration of neurons in Parkinson’s disease (PD). Baicalein has shown neuroprotective effects in PD animal models. In this study, we investigated the effect of baicalein on K-ATP channels and the underlying mechanisms in rotenone-induced apoptosis of SH-SY5Y cells. K-ATP currents were recorded from SH-SY5Y cells using whole-cell voltage-clamp recording. Drugs dissolved in the external solution at the final concentration were directly pipetted onto the cells. We showed that rotenone and baicalein opened K-ATP channels and increased the current amplitudes with EC 50 values of 0.438 μM and 6.159 μM, respectively. K-ATP channel blockers glibenclamide (50 μM) or 5-hydroxydecanoate (5-HD, 250 μM) attenuated the protective effects of baicalein in reducing reactive oxygen species (ROS) content and increasing mitochondrial membrane potential and ATP levels in rotenone-injured SH-SY5Y cells, suggesting that baicalein protected against the apoptosis of SH-SY5Y cells by regulating the effect of rotenone on opening K-ATP channels. Administration of baicalein (150, 300 mg·kg −1 ·d −1 , i.g.) significantly inhibited rotenone-induced overexpression of SUR1 in SN and striatum of rats. We conducted surface plasmon resonance assay and molecular docking, and found that baicalein had a higher affinity with SUR1 protein ( K D = 10.39 μM) than glibenclamide ( K D = 24.32 μM), thus reducing the sensitivity of K-ATP channels to rotenone. Knockdown of SUR1 subunit reduced rotenone-induced apoptosis and damage of SH-SY5Y cells, confirming that SUR1 was an important target for slowing dopaminergic neuronal degeneration in PD. Taken together, we demonstrate for the first time that baicalein attenuates rotenone-induced SH-SY5Y cell apoptosis through binding to SUR1 and activating K-ATP channels.

This study aims to prepare a stable crystal-co-agglomeration (CCA) process for combining the antibiotics trimethoprim (TMP) and the anti-inflammatory niflumic acid (NFA) as well as the enhancement of powder properties. A novel TMP-NFA salt monohydrate was synthesized and characterized through multitechniques for the first time. Subsequently, the antibacterial effectiveness of TMP-NFA salt monohydrate against Staphylococcus aureus and Shigella flexneri was found to be improved (P < 0.05) compared with that of TMP at certain concentrations, achieving a synergistic effect of TMP and NFA. Based on these findings, spherical agglomerates of TMP-NFA salt monohydrate with superior powder properties including improved flowability (Carr's index decreased by 37.5% and Hausner's ratio decreased by 16.3%) and tabletability were produced using an efficient CCA process. Hence, the optimized spherical agglomerates of the drug-drug salt technique provide a promising approach to simultaneously enhance the powder properties and synergistic effect of active pharmaceutical ingredients. The development of such drug-drug salts holds great potential for advancing pharmaceutical formulations and therapeutic outcomes.

Dermal fibroblasts (dFBs) defend against deep bacterial skin infections by differentiating into preadipocytes (pAds) that produce the antimicrobial peptide cathelicidin; this differentiation is known as the dermal reactive adipogenesis response. However, the role of dFBs in fungal infection remains unknown. Here, we found that cathelicidin-producing pAds were present in high numbers in skin lesions from patients with cutaneous Candida granulomas. Second, we showed that dermal Candida albicans (C. albicans) infection in mice robustly triggered the dermal reactive adipogenesis response and induced cathelicidin expression, and inhibition of adipogenesis with pharmacological inhibitors of peroxisome proliferator-activated receptor γ (PPARγ) impaired skin resistance to C. albicans. In vitro, C. albicans products induced cathelicidin expression in pAds, and differentiating pAds markedly suppressed the growth of C. albicans by producing cathelicidin. Finally, we showed that C. albicans induced an antimicrobial response in pAds through the FGFR-MEK-ERK pathway. Together, our data reveal a previously unknown role of dFBs in the defense against skin infection caused by C. albicans.

Heart failure with preserved ejection fraction (HFpEF) is a morbid, fatal, and common syndrome for which lack of evidence-based therapies. Salvianolic acid A (SAA), a major active ingredient of Salvia miltiorrhiza Burge, has shown potential to protect against cardiovascular diseases. This study aims to elucidate whether SAA possessed therapeutic activity against HFpEF and explore the potential mechanism. HFpEF mouse model was established infusing a combination of high-fat diet (HFD) and Nω-nitro-L-arginine methyl ester (L-NAME) for 14 weeks. After 10 weeks of feeding, HFpEF mice were given SAA (2.5, 5, 10 mg/kg) via oral gavage for four weeks. Body weight, blood pressure, blood lipids, glucose tolerance, exercise performance, cardiac systolic/diastolic function, cardiac pathophysiological changes, and inflammatory factors were assessed. Experimental results showed that SAA reduced HFpEF risk factors, such as body weight gain, glucose intolerance, lipid disorders, and increased exercise tolerance in HFpEF mice. Moreover, SAA not only relieved myocardial hypertrophy and fibrosis by reducing interventricular septal wall thickness, left ventricular posterior wall thickness, left ventricular mass, heart index, cardiomyocyte cross-sectional area and cardiac collagen content, but also improved cardiac diastolic function via reducing E/E′ ratio. Finally, SAA inhibited TLR2/TLR4-mediated Myd88 activation and its downstream molecules TRAF6 and IRAK4, which decreases the release of proinflammatory cytokines and mediators through NF-κB and p38 MAPK pathways. In conclusion, SAA could attenuate cardiac inflammation and cardiac disfunction by TLR/Myd88/TRAF/NF-κB and p38MAPK/CREB signaling pathways in HFpEF mice, which provides evidence for SAA as a potential drug for treatment of HFpEF in clinic.

Abstract Background Numerous fundamental and clinical investigations have showcased the correlation and interplay mechanism between coronary artery disease (CAD) and pulmonary arterial hypertension (PAH). We aimed to investigate diagnostic indicators and the correlation between immune response and diagnostic indicators.Methods To conduct additional differential expression analysis and weighted gene coexpression network analysis (WGCNA), we obtained CAD and PAH data from the Gene Expression Omnibus (GEO) database. Next, we employed shared genes to conduct enrichment analysis, construct a protein-protein interaction (PPI) network, and subsequently identify diagnostic biomarkers through the utilization of three machine learning algorithms. The diagnostic biomarkers were utilized for conducting logistic regression analysis and constructing a nomogram. Then, we compared the expression differences and their respective diagnostic effects. The evaluation of immune infiltration was conducted finally.Results By intersecting 671 genes that were differentially expressed in CAD and 2052 genes that were key module genes in PAH, we identified 67 genes that were common to both conditions. These shared genes were mainly enriched in signaling pathways associated with the activation of leukocytes and the regulation of inflammation. We further identified 26 genes through PPI network construction. Afterwards, three machine learning algorithms were utilized to choose two candidate biomarkers, namely DPYD and CPT1A. The two possible indicators showed improved diagnostic effectiveness and suggested a statistically significant positive correlation with macrophages in individuals with progressive CAD.Conclusion In this study, we have conducted the first research to identify early diagnostic biomarkers for the advancement of CAD in association with PAH. This was achieved by employing a variety of bioinformatic methods and machine learning algorithms. Possible therapeutic targets may exist due to the presence of a favorable correlation between diagnostic biomarkers and immune cells.

BACKGROUND AND OBJECTIVE:Bioprostheses are the most common prostheses used for valve replacement in the Western medicine. The major flaw of bioprostheses is the occurrence of structural valve deterioration (SVD). This study aimed to assess the pathological features of porcine aortic valve (PAV)-SVD based on histomorphological and immunopathological characteristics of a large cohort of patients.METHODS:Histopathological data of 109 cases with resected PAV were collected. The type and amount of infiltrated cells were evaluated in the different types of bioprosthetic SVD by immunohistochemical staining.RESULTS:The most common cause of SVD was calcification, leaflet tear, and dehiscence (23.9%, 19.3%, and 18.3%, respectively). Immunohistochemical staining demonstrated that macrophages were infiltrated in the calcified, lacerated and dehiscence PAV, in which both M1 and M2 macrophages were existed in the calcified PAV. Importantly, the higher content of M1 macrophages and less content of M2 macrophages were found in the lacerated and dehiscence PAV, and MMP-1 expression was mainly found in the lacerated PAV. The endothelialization rate of leaflet dehiscence was higher than that of calcified and lacerated leaflets. A large number of CD31+/CD11b+ cells was aggregated in the spongy layer in the lacerated and dehiscence PAV.CONCLUSION:Cell regeneration and infiltration is a double edged sword for the PAV deterioration. Macrophage infiltration is involved in the different types of SVD, while only MMP-1 expression is involved in lacerated leaflets. The macrophage subtype of circulating angiogenic cells in dehiscence and tear PAV could be identified, which could reserve macrophages in the PAV-SVD.

There is a new form of puerarin, puerarin-V, that has recently been developed, and it is unclear whether puerarin-V has a cardioprotective effect on diabetic cardiomyopathy (DCM). Here, we determined whether puerarin-V had any beneficial influence on the pathophysiology of DCM and explored its possible mechanisms. By injecting 30 mg/kg of STZ intraperitoneally, diabetes was induced in rats. After a week of stability, the rats were injected subcutaneously with ISO (5 mg/kg). We randomly assigned the rats to eight groups: (1) control; (2) model; (3) metformin; (4–6) puerarin-V at different doses; (7) puerarin (API); (8) puerarin injection. DCM rats were found to have severe cardiac insufficiency (arrythmia, decreased LVdP/dt, and increased E/A ratio). In addition, cardiac injury biomarkers (cTn-T, NT-proBNP, AST, LDH, and CK-MB), inflammatory cytokines (IL-1β, IL-18, IL-6, and TNF-α), and oxidative damage markers (MDA, SOD and GSH) were markedly increased. Treatment with puerarin-V positively adjusts these parameters mentioned above by improving cardiac function and mitochondrial respiration, suppressing myocardial inflammation, and maintaining the structural integrity of the cardiac muscle. Moreover, treatment with puerarin-V inhibits the P2X7 receptor-mediated pyroptosis pathway that was upregulated in diabetic hearts. Given these results, the current study lends credence to the idea that puerarin-V can reduce myocardial damage in DCM rats. Furthermore, it was found that the effect of puerarin-V in diabetic cardiomyopathy is better than the API, the puerarin injection, and metformin. Collectively, our research provides a new therapeutic option for the treatment of DCM in clinic.

Objective The pathological evaluation is an important aspect in the preclinical research of cardiovascular devices.The aim of the study was to set up a pathological evaluation strategy for preclinical safety study of annuloplasty rings.Methods Total 22 annuloplasty rings were implanted separately in 22 adult male sheep,including 17 sheep in the test group of two kinds of new rings and 5 sheep in the control group.The implant position was the mitral valve in 17 sheep and the tricuspid valve in 5 sheep.When the animals were sacrificed 20 weeks after surgery,pathological examination was performed to evaluate the integrity of the annuloplasty rings,inflammatory reaction,endothelization,fibrous sheath,pannus,thrombosis at the gross,histological and ultrastructural levels.We also evaluated the injury of the heart and remote organs.Results All rings appeared well implanted at the mitral or tricuspid valves without any surgical injury on valves and coronary arteries.The annulopasty rings were well in the structural integrity and encapsulated by a thin fibrous sheath without thrombus and pannus.A few lymphocytes,macrophages and multinuclear giant cells were observed around the rings in all sheep while neutrophil infiltration was found only in 1 sheep of the test group.Scanning electron microscopy showed almost complete endothelization on the surface of rings.There was no significant difference of endothelization rate between the two groups [(92.0 ± 8.1) ％ vs.(97.0 ±2.4) ％,P =0.081].Other changes included focal myocardial necrosis in 6 sheep,kidney infarction in 1 sheep and granulomatous inflamation of liver in 1 sheep.Unexpected death occurred in 4 sheep (3 in the test group and 1 in the control group) at the 2nd,11th,12th and 13th week after surgery respectively.Their causes of death were regarded as pulmonary infection while autopsy also found incomplete fibrous sheath and lower endothelization rate of 5％ to 60％ in 3 sheep and a micro thrombi in 1 sheep.Conclusion A good pathological evaluation about annuloplasty rings should focus on the structural integrity,biocompatibility and complication of the heart and other organs at several morphological levels.It is important for preclinical safety study to differentiate adverse effect of annuloplasty rings,surgical injury and infection as the cause of complications and death.

Baicalein, a flavonoid with potent antioxidant and anti‐inflammatory properties, has been shown to have neuroprotective effects. But baicalein has a pool dissolvability and scarcely dissolve in water. Thus,our topic group studied the crystal form of the chemical composition of baicalein. The result showed that baicalein possessed polymorphism. Moreover, β crystal form of baicalein was determined to be a superiority drug crystal because of its dominant position in stability and absorbance by constancy and biological test. So β crystal form of baicalein was used in this experiment. In rats, the behavioral and immunohistochemical manifestations after unilateral 6‐OHDA lesion were determined. Baicalein could significantly attenuate muscle tremor of 6‐OHDA lesioned rats (the burst frequency and amplitude are 13.43%, 35.18% compared to 6‐OHDA group), but could not reduce apomorphine (APO)‐induced rotations. Moreover, baicalein treatment could also increase tyrosine hydroxylase (TH)‐positive neurons (265.52% compared to 6‐OHDA group) and ameliorate the severe increase of glial fibrillary acidic protein (GFAP) immunoreactivity (70.23% compared to 6‐OHDA group) in the substantia nigra. Therefore, baicalein can be a promising candidate for prevention or treatment of Parkinson’s disease, owing to its anti‐apoptotic, pro‐differentiation and anti‐inflammatory action.Grant Funding Source: This work was supported by the Research Special Fund for Public Welfare Industry of Health (No. 200802041) and National Significant Projects of New Drugs Creation (No. 2009ZM09501‐021).